Studies presented at the recent International AIDS Conference demonstrate that combination therapy with inhibitors of the viral protease and reverse transcriptase produce profound and durable declines in the viral RNA present in plasma and increases in CD4 counts. Several investigators have even proposed that long term suppression with agents now available may result in eradication of virus and cure of disease. However, although these regimens produce very powerful antiviral effects in the short term, several features of drug dosing and medication adherence, viral replication, as well as pharmacokinetic variability may prevent the realization of this goal. First, the regimens require the administration of between 20 to 30 pills/day and must be taken over the course of at least several years. Second, variants resistant to all of these drugs have been described. Third, there is considerable variability both between and within individuals with regard to the drug levels maintained with the same does. Therefore, a major concern is the ability of HIV-infected people to take this large number of medications regularly over the long term; less than perfect adherence will no doubt be manifested at some time by the majority of patients. Fluctuating drug levels due to variable pharmacokinetics are also expected. We believe that over the long course of therapy anticipated for these compounds, each of these variables will play a role in determining their overall effectiveness. It is the impact of these factors on treatment efficacy and the development of antiviral resistance that is the focus of the studies proposed in this application. Specifically, we will: I. Test the hypothesis that altered patterns of medication adherence with protease inhibitors lead to the development of resistance and define the level of medication adherence necessary to maintain a clinically relevant antiviral effect. II. Identify the barriers to medication adherence. III. Define patient factors that influence the concentrations of protease inhibitors using minimally-invasive strategies.